Robust photoregulation of GABA A receptors by allosteric modulation with a propofol analogue

Lan Yue; Michal Pawlowski; Shlomo S. Dellal; An Xie; Feng Feng; Thomas S. Otis; Karol S. Bruzik; Haohua Qian; David R. Pepperberg

doi:10.1038/ncomms2094

Robust photoregulation of GABA A receptors by allosteric modulation with a propofol analogue

Lan Yue, Michal Pawlowski, Shlomo S. Dellal, An Xie, Feng Feng, Thomas S. Otis, Karol S. Bruzik, Haohua Qian, David R. Pepperberg

Research output: Contribution to journal › Article › peer-review

53 Scopus citations

Abstract

Photochemical switches represent a powerful method for improving pharmacological therapies and controlling cellular physiology. Here we report the photoregulation of GABA_A receptors (GABA_A Rs) by a derivative of propofol (2,6-diisopropylphenol), a GABA_AR allosteric modulator, which we have modified to contain photoisomerizable azobenzene. Using α₁β₂γ₂GABA_ARs expressed in Xenopus laevis oocytes and native GABA_ARs of isolated retinal ganglion cells, we show that the trans-azobenzene isomer of the new compound (trans-MPC088), generated by visible light (wavelengths ∼440 nm), potentiates the γ-aminobutyric acid-elicited response and, at higher concentrations, directly activates the receptors. cis-MPC088, generated from trans-MPC088 by ultraviolet light (∼365 nm), produces little, if any, receptor potentiation/activation. In cerebellar slices, MPC088 co-applied with γ-aminobutyric acid affords bidirectional photomodulation of Purkinje cell membrane current and spike-firing rate. The findings demonstrate photocontrol of GABA_ARs by an allosteric ligand, and open new avenues for fundamental and clinically oriented research on GABA_ARs, a major class of neurotransmitter receptors in the central nervous system.

Original language	English (US)
Article number	1095
Journal	Nature communications
Volume	3
DOIs	https://doi.org/10.1038/ncomms2094
State	Published - 2012
Externally published	Yes

Bibliographical note

Funding Information:
We thank Drs Robert F. Standaert, Hélène A. Gussin and Deborah M. Little for helpful discussions; Dr Martin Wallner for providing cDNA for the α4, β3, β3(N265M) and δ GABAAR subunits; and Dr Matthew Shtrahman, Ms. Vivy Tran, Ms. Tara Nguyen and Dr Joyce Wondolowski for technical assistance. Supported by NIH grants EY016094, EY001792 and AA01973; the Daniel F. and Ada L. Rice Foundation (Skokie, IL); Hope for Vision (Washington, DC); the Beckman Initiative for Macular Research (Los Angeles, CA); the American Health Assistance Foundation (Clarksburg, MD); Research to Prevent Blindness (New York, NY); and by award UL1RR029879 from the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS).

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title = "Robust photoregulation of GABA A receptors by allosteric modulation with a propofol analogue",

abstract = "Photochemical switches represent a powerful method for improving pharmacological therapies and controlling cellular physiology. Here we report the photoregulation of GABAA receptors (GABAA Rs) by a derivative of propofol (2,6-diisopropylphenol), a GABAAR allosteric modulator, which we have modified to contain photoisomerizable azobenzene. Using α1β2γ2GABAARs expressed in Xenopus laevis oocytes and native GABAARs of isolated retinal ganglion cells, we show that the trans-azobenzene isomer of the new compound (trans-MPC088), generated by visible light (wavelengths ∼440 nm), potentiates the γ-aminobutyric acid-elicited response and, at higher concentrations, directly activates the receptors. cis-MPC088, generated from trans-MPC088 by ultraviolet light (∼365 nm), produces little, if any, receptor potentiation/activation. In cerebellar slices, MPC088 co-applied with γ-aminobutyric acid affords bidirectional photomodulation of Purkinje cell membrane current and spike-firing rate. The findings demonstrate photocontrol of GABAARs by an allosteric ligand, and open new avenues for fundamental and clinically oriented research on GABAARs, a major class of neurotransmitter receptors in the central nervous system.",

author = "Lan Yue and Michal Pawlowski and Dellal, {Shlomo S.} and An Xie and Feng Feng and Otis, {Thomas S.} and Bruzik, {Karol S.} and Haohua Qian and Pepperberg, {David R.}",

note = "Funding Information: We thank Drs Robert F. Standaert, H{\'e}l{\`e}ne A. Gussin and Deborah M. Little for helpful discussions; Dr Martin Wallner for providing cDNA for the α4, β3, β3(N265M) and δ GABAAR subunits; and Dr Matthew Shtrahman, Ms. Vivy Tran, Ms. Tara Nguyen and Dr Joyce Wondolowski for technical assistance. Supported by NIH grants EY016094, EY001792 and AA01973; the Daniel F. and Ada L. Rice Foundation (Skokie, IL); Hope for Vision (Washington, DC); the Beckman Initiative for Macular Research (Los Angeles, CA); the American Health Assistance Foundation (Clarksburg, MD); Research to Prevent Blindness (New York, NY); and by award UL1RR029879 from the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS).",

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AU - Yue, Lan

AU - Pawlowski, Michal

AU - Dellal, Shlomo S.

AU - Xie, An

AU - Feng, Feng

AU - Otis, Thomas S.

AU - Bruzik, Karol S.

AU - Qian, Haohua

AU - Pepperberg, David R.

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N2 - Photochemical switches represent a powerful method for improving pharmacological therapies and controlling cellular physiology. Here we report the photoregulation of GABAA receptors (GABAA Rs) by a derivative of propofol (2,6-diisopropylphenol), a GABAAR allosteric modulator, which we have modified to contain photoisomerizable azobenzene. Using α1β2γ2GABAARs expressed in Xenopus laevis oocytes and native GABAARs of isolated retinal ganglion cells, we show that the trans-azobenzene isomer of the new compound (trans-MPC088), generated by visible light (wavelengths ∼440 nm), potentiates the γ-aminobutyric acid-elicited response and, at higher concentrations, directly activates the receptors. cis-MPC088, generated from trans-MPC088 by ultraviolet light (∼365 nm), produces little, if any, receptor potentiation/activation. In cerebellar slices, MPC088 co-applied with γ-aminobutyric acid affords bidirectional photomodulation of Purkinje cell membrane current and spike-firing rate. The findings demonstrate photocontrol of GABAARs by an allosteric ligand, and open new avenues for fundamental and clinically oriented research on GABAARs, a major class of neurotransmitter receptors in the central nervous system.

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Robust photoregulation of GABA A receptors by allosteric modulation with a propofol analogue

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